Product tampering occurs when a dosage form is manipulated to achieve an objective in ways that is not intended per dosing instructions. It may involve drug abusers who tamper with the dosage form to obtain euphoria, or non-abusers such as patients and caregivers who innocently tamper with the dosage form to address legitimate concerns. For example, an elderly patient may break a dosage form to facilitate swallowing or a caregiver may break a dosage form to reduce the therapeutic dose.
Prescription medications are being abused at an alarming rate. The most commonly abused classes of prescription drug products are opioids (narcotics), sedatives/hypnotics, stimulants, and tranquilizers. The most commonly abused over-the-counter drugs are decongestants, antihistamines and cough medicines. An estimated 52 million people have used prescription drugs for nonmedical reasons at least once in their lifetimes.
Particularly, abuse of prescription painkillers is a growing, public health problem that has been steadily worsening as reflected in increased treatment admissions, emergency room visits, and overdose deaths. About 164 million patients/year visit the doctor office for pain of which 20% receive opiate prescriptions for pain treatment. Number of opiate prescriptions has been steadily increasing since 1991. In 2013 alone, 230 million opioid prescriptions were dispensed. The pain management market generated $7.3 billion in US sales in 2012. The market is predicted to increase to $9.8 billion by 2018 and to $11.3 billion by 2023.
In 2010, more than 40% of all drug poisoning deaths involved opioid analgesics, and the number of overdose deaths involving opioid analgesics has more than tripled since 1999. The CDC's latest figures show that 16,500 people died from overdoses tied to common narcotic pain relievers in 2010. Over dosage of opiates occurs due to intentional or unintentional tampering of opiate drug products. Abusers tamper with dosage form to obtain euphoria, while patients/caregivers manipulate dosage forms to facilitate dosing. Pain relievers, such as OxyContin® and Vicodin®; anti-depressants, such as Xanax® and Valium®, and stimulants, such as Concerta®, Adderall®, are the most commonly abused prescription drugs.
While drug abuse has been common with all dosage forms, modified release products have been particularly attractive to drug abusers due to the high drug content in the dosage forms. When these dosage forms are tampered with or altered, they may lead to more rapid release of the therapeutic agent, which in turn may provide the drug abusers with greater euphoria that they desperately desire.
To address the drug abuse epidemic, pharmaceutical companies have started to develop abuse deterrent formulations and the U.S. Food and Drug Administration (FDA) has also issued a guideline to encourage development of more effective tamper-resistant formulations. Abuse deterrent formulations are designed to thwart deliberate attempts by drug-abusers to extract the active ingredient or blunt the euphoric effects from unapproved methods of administration.
Common methods of drug abuse include: (1) oral ingestion, where the dosage form is chewed, to destroy the release controlling matrix and deliver high doses of therapeutic agent into the gastrointestinal tract, and swallowed, with or without co-ingestion of alcohol; (2) intravenous injection, which involves extraction of the therapeutic agent from the dosage form using an appropriate solvent, followed by injection of the therapeutic agent directly into the blood stream; (3) nasal snorting, where the dosage form is crushed, milled, or ground into a fine powder and administered intra-nasally to facilitate rapid drug absorption through the lining of the nasal passages; and (4) smoking, where the therapeutic agent is vaporized for inhalation by subjecting the dosage form to heat.
In addition, dosage forms, particularly modified release dosage forms, are relatively large in size and may pose a dosing challenge to many people including the elderly and young. Often, patients and caregivers may break the dosage form to reduce the size. By doing so, they inadvertently compromise the release controlling mechanism of the dosage form and potentially lead to dose dumping, often with adverse consequences.
To circumvent dosage form tampering, many tamper resistant formulations have been described.
U.S. Pat. No. 7,510,726 describes a therapeutic pharmaceutical composition comprising a mixture consisting of at least one opioid analgesic, gel forming polyethylene oxide, and at least one disintegrant. Due to the physical properties of the gel forming polymer, the extended release properties of the disclosed dosage form is expected to be compromised upon mastication and not prevent abuse by chewing and swallowing.
U.S. Pat. No. 7,771,707 describes a solid abuse deterrent pharmaceutical composition of a pharmaceutically active agent prone to abuse, and one or more fatty acids or fatty amines present in molar excess relative to the pharmaceutically active agent. As taught, the fatty acids and fatty acid amines which impart lipophilicity on the drug substance may be susceptible to physical instability.
U.S. Pat. No. 7,776,314 describes parenteral abuse-proofed solid dosage form for oral administration, comprising one or more active ingredients with potential for abuse, and at least one viscosity-increasing agent. Invention deters only abuse by injection.
U.S. Pat. No. 8,075,872 describes an abuse resistant dosage form thermoformed by extrusion and having a breaking strength of at least 500 N, which contains a mixture of one or more active ingredients with abuse potential, polyalkylene oxides, physiologically acceptable auxiliary substances, and optionally wax and cellulosic derivatives. The disclosed dosage form contains low tg hydrophilic polymers that may not withstand mastication when exposed to saliva due to plasticization.
U.S. Pat. No. 8,409,616 describes a therapeutic pharmaceutical composition comprising a water-soluble drug susceptible to abuse, a gel forming polymer and a disintegrant. As taught, the gel forming polymers based on polyethylene oxide are susceptible to chewing and mastication upon contact with saliva.
U.S. Pat. No. 8,449,909 describes a therapeutically effective pharmaceutical composition comprising solid microparticles, wherein the microparticles comprise an active agent, one or more fatty acids, and one or more carrier materials selected from waxes or wax-like substances. The fatty acids and fatty acid amines, as taught, impart lipophilicity on the drug substance but may not ensure physical stability upon storage. U.S. Patent Application Publication 2008/0075770 describes a monolithic solidified oral dosage form prepared by a thermal process comprising a therapeutic agent and a hydrophilic polymer. The disclosed drug molecules incorporated in a hydrophilic polymeric matrix have a tendency to diffuse when mobility of the polymer is increased due to solvent or temperature effect, thereby increasing extractability.
U.S. Pat. No. 8,486,448 describes a controlled release formulation comprising a core comprising a superabsorbent material, a controlled release coat surrounding the core; and a plurality of controlled release microparticles containing a pharmaceutically active agent. This abuse deterrent relies on a hard coating that may be susceptible to extraction by both aqueous and organic solvents.
U.S. Pat. No. 8,202,542 describes an abuse resistant opioid drug-ion exchange resin complexes having hybrid coatings containing a cured polyvinylacetate polymer and a pH-dependent enteric coating layer mixed therein. As taught, these polymer coatings are soluble in aqueous or organic solvents which would make the dosage form susceptible abuse by extraction.
U.S. Patent Application Publication 2011/0020451 describes a tamper-resistant thermoformed pharmaceutical dosage form having a breaking strength of at least 300 N and comprising an opioid, a physiologically acceptable acid and a polyalkylene oxide. The disclosed dosage form is expected to be susceptible to abuse by chewing and swallowing.
U.S. Patent Application Publication 2012/0148672 describes a coated modified release opioid-ion exchange resin complex comprising a pharmaceutically effective amount of an opioid bound to a pharmaceutically acceptable ion exchange resin complex; and a pH-independent, high tensile strength, water permeable, water insoluble, diffusion barrier coating. As disclosed, the coating is expected to dissolve in organic solvents and high aqueous pH, which would make the dosage form reduce extraction by the complexing ion exchange resin only.
As a result, in spite of the various tamper-resistant formulation approaches mentioned above, there is still a need for improved abuse deterrent formulations that better prevent common methods of dosage form tampering and associated drug abuse administration routes with or without the incorporation of aversive agents and agonist/antagonists in the dosage form.
In particular, the present invention eliminates or reduces all forms of tampering, and hence all modes of abuse. The invention relates to an erodible dosage form that has a dry core which hydrates on the surface upon exposure to extraction fluid to form a thin gel layer that limits water penetration into the core. The dosage form also has a synchronized barrier system that provides it with plasticity and hardness that renders the dosage form resistant to chewing, crashing and grainding, and volatilization.